Loss of muscle strength (i.e. weakness) associated with aging is a huge problem as it limits physical independence and is a major factor in the development of disability. Many of the changes that accompany the loss of strength with aging coincide with those observed following immobilization. Thus, immobilization is a model that is particularly well suited to examine losses in strength seen in an aging population. Losses of strength are mediated by changes in both muscular (e.g. atrophy) and neural properties (e.g. cortical inhibition). While there have been extensive studies examining muscular properties, little is known regarding the changes in cortical properties associated with the loss of strength. The potential role of cortical mechanisms in mediating strength is supported by the known effects of motor imagery on increasing strength. More specifically, intracortical facilitation and inhibition may be important neural mechanisms in mediating strength. Intracortical facilitation and inhibition is assessed using paired-pulse transcranial magnetic stimulation, and our pilot data suggests that both aging and immobilization increases long-interval intracortical inhibition (LICI) and the immobilization-induced increase in LICI is associated with the loss of strength. Our central hypothesis is that a high level of LICI is an important neurophysiologic determinant of muscle strength. We will test this hypothesis by accomplishing the following three specific aims: 1) to determine the association between the immobilization-induced changes in intracortical properties and the reduction in muscle strength and central activation;2) to evaluate the effect of motor imagery training on minimizing the immobilization-induced changes in intracortical properties and the reduction in muscle strength and central activation;and 3) to compare differences in intracortical properties between young adults, older healthy adults, and prefrail older adults, and evaluate the interrelationship between age-related differences in intracortical properties and muscle strength and central activation. Understanding the specific neural mechanisms underlying the loss of muscle strength is critical to improving rehabilitation strategies. PUBLIC HEALTH RELEVANCE: Muscle weakness is a common clinical phenomena observed in association with aging and disuse, weakness is associated with disability development, reduced functional capacity, and even mortality. This research will identify the intracortical facilitatory and inhibitory properties in mediating the loss of strength associated with both immobilization and aging. Developing an understanding of the neural mechanisms mediating muscle weakness will contribute to the development of interventions to promote muscle function.